10-hydroxywarfarin and 7-hydroxywarfarin

10-hydroxywarfarin has been researched along with 7-hydroxywarfarin* in 3 studies

Other Studies

3 other study(ies) available for 10-hydroxywarfarin and 7-hydroxywarfarin

ArticleYear
Analytical aspects of achiral and cyclodextrin-mediated capillary electrophoresis of warfarin and its two main derivatives assisted by theoretical modeling.
    Journal of chromatography. A, 2015, Jan-16, Volume: 1377

    Several distinct analytical issues have been addressed by performing capillary electrophoresis-based separations of the warfarin, 7-hydroxywarfarin and 10-hydroxywarfarin in an achiral and cyclodextrin-containing media. The measurements were conducted across a range of pH in order to find optimum conditions for achiral and chiral separations. The values of acid dissociation constant (pKa) have been determined and compared. Subsequently, after performing a series of mobility shift assays at different pH and cyclodextrin concentration, the pKa values ascribed to diastereomeric complexes with methyl-β-cyclodextrin have been estimated. The significant pKa shifts upon complexation have been noticed for warfarin - up to 1.5 pH units, and only subtle for 10-hydroxywarfarin. A new approach that allows the estimation of association percentage based on the electrophoretic mobility curves has been also demonstrated. The complex mechanism of chiral separation has been found to be responsible for the observed migration profile, relying on a combined equilibrium between complexation/partition and protonation/deprotonation phenomena. The occurrence of the pKa-related migration order reversal has been demonstrated in achiral medium between warfarin and 7-hydroxywarfarin, and in chiral medium between enantiomers, causing a drop in enantioselectivity at specific pH. In parallel, the density functional theory-based calculations have been performed in order to obtain the structures of warfarin and its derivatives as well as to rationalize the shifts in pKa values.

    Topics: Cyclodextrins; Electrophoresis; Electrophoresis, Capillary; Electrophoretic Mobility Shift Assay; Hydrogen-Ion Concentration; Models, Theoretical; Stereoisomerism; Warfarin

2015
Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin.
    Chemical research in toxicology, 2010, May-17, Volume: 23, Issue:5

    Coumadin (R/S-warfarin) anticoagulant therapy poses a risk to over 50 million Americans, in part due to interpersonal variation in drug metabolism. Consequently, it is important to understand how metabolic capacity is influenced among patients. Cytochrome P450s (P450 or CYP for a specific isoform) catalyze the first major step in warfarin metabolism to generate five hydroxywarfarins for each drug enantiomer. These primary metabolites are thought to reach at least 5-fold higher levels in plasma than warfarin. We hypothesized that hydroxywarfarins inhibit the hydroxylation of warfarin by CYP2C9, thereby limiting enzymatic capacity toward S-warfarin. To test this hypothesis, we investigated the ability of all five racemic hydroxywarfarins to block CYP2C9 activity toward S-warfarin using recombinant enzyme and human liver microsomes. We initially screened for the inhibition of CYP2C9 by hydroxywarfarins using a P450-Glo assay to determine IC(50) values for each hydroxywarfarin. Compared to the substrate, CYP2C9 bound its hydroxywarfarin products with less affinity but retained high affinity for 10- and 4'-hydroxywarfarins, products from CYP3A4 reactions. S-Warfarin steady-state inhibition studies with recombinant CYP2C9 and pooled human liver microsomes confirmed that hydroxywarfarin products from CYP reactions possess the capacity to competitively inhibit CYP2C9 with biologically relevant inhibition constants. Inhibition of CYP2C9 by 7-hydroxywarfarin may be significant given its abundance in human plasma, despite its weak affinity for the enzyme. 10-Hydroxywarfarin, which has been reported as the second most abundant plasma metabolite, was the most potent inhibitor of CYP2C9, displaying approximately 3-fold higher affinity than S-warfarin. These results indicate that hydroxywarfarin metabolites produced by CYP2C9 and other CYPs may limit metabolic capacity toward S-warfarin through competitive inhibition. Subsequent processing of hydroxywarfarins to secondary metabolites, such as hydroxywarfarin glucuronides, could suppress product feedback inhibition, and therefore could play an important role in the modulation of metabolic pathways governing warfarin inactivation and elimination.

    Topics: Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Humans; Kinetics; Microsomes, Liver; Recombinant Proteins; Stereoisomerism; Warfarin

2010
Determination of warfarin enantiomers and hydroxylated metabolites in human blood plasma by liquid chromatography with achiral and chiral separation.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2005, Apr-25, Volume: 818, Issue:2

    An assay comprising two simple, selective and isocratic HPLC methods with UV detection was developed and validated for measuring warfarin enantiomers and all five warfarin monohydroxylated metabolites in patient blood plasma. Following liquid/liquid extraction from 1 ml of blood plasma a baseline separation of analytes was achieved on chiral (alpha(1) acid glycoprotein - AGP) and achiral (C(18)) column. Both methods were consistent (R.S.D.<6.9% for warfarin enantiomers and<8.9% for monohydroxylated metabolites) and linear (r>0.998). The limits of detection were 25 ng/ml for warfarin enantiomers, 25 ng/ml for 4'-, 10-, 6- and 7-hydroxywarfarin, 35 ng/ml for 8-hydroxywarfarin and 50 ng/ml for racemic warfarin. In a clinical study in 204 patients, it was confirmed that the assay is appropriate for evaluation of influences of genetic polymorphisms, demographic factors and concomitant drug treatment on warfarin metabolism.

    Topics: Anticoagulants; Chromatography, High Pressure Liquid; Drug Stability; Humans; Stereoisomerism; Thromboembolism; Warfarin

2005